The long-term goal of HL-46493 is to understand how substances released by contracting skeletal muscles and sympathetic nerves interact and regulate blood flow to the active muscles. This renewal focuses on local and systemic responses to "mismatches" between muscle blood flow, O2 delivery and metabolism to explore in humans a) whether the pressor response to rhythmic exercise during muscle hypoperfusion improves blood flow to active muscles;b) the potential vasodilator "error signals" associated with hypoperfusion in active muscles;c) the interactions between these responses;and d) the extent to which challenges to skeletal muscle O2 delivery with hypoxia vs. hypoperfusion evoke similar compensatory adjustments. In this context, the following specific aims will be addressed: 1) We will use a small intra- arterial catheter/balloon system to create graded skeletal muscle hypoperfusion during rhythmic handgripping to evaluate whether the pressor response to exercise with muscle hypoperfusion improves blood flow to the active muscles. We hypothesize that the rise in vasoconstricting muscle sympathetic nerve activity (MSNA) evoked by the combination of rhythmic exercise and hypoperfusion prevents the pressor response from improving blood flow to the contracting muscles. 2) Using the catheter/balloon system, we will measure the local vasodilator responses to muscle hypoperfusion during exercise and use pharmacological tools to explore their nature. We hypothesize that local vasodilator responses to rhythmic exercise with hypoperfusion serve to maintain muscle blood flow during mild and moderate but not heavy rhythmic handgripping when MSNA is likely to rise. We also hypothesize that adenosine (perhaps along with NO) will be the main factor responsible for the compensatory dilation. 3) We will test whether the compensatory vasodilator signals that maintain O2 delivery to active muscles during exercise with mild hypoxia are the same or different than those that cause compensatory vasodilation during normoxic exercise with hypoperfusion. We hypothesize that adenosine (perhaps along with NO) will be the main factor responsible for the compensatory dilation under both circumstances. Summary and Significance: Muscle blood flow is a key determinant of exercise capacity, and it is unknown how systemic sympathoexcitation and local vasodilator responses to exercise with either hypoperfusion or hypoxia interact to regulate blood flow to contracting human skeletal muscles. We propose novel and innovative strategies to address a number of currently unresolved issues and controversies related to these topics in humans.